Thiobarbituric compound



Patented Aug. 25, 1942 UNITED STATES PATENT OFFICE N Drawing. Application July 21, 1941, Serial No. 403,366

6 Claims.

This invention relates to thiobarbituric compounds and more particularly to l-methylallyl thiobarbituric compounds.

The compositions of this invention are represented by the following formula:

(1) CH2=CHCH o O-NH CH3 R o 0-1 X in which R is a radical selected from the class consisting of the n propyl and the n-butyl radicals and X represents a member of the class consisting of hydrogen (if the compound is an acid) and (if the compound is a salt) an alkali metal, such as sodium, an equivalent of analkaline-earth metal, such as calcium, ammonium, monoalkyl ammonium, such as '-NH3CH3, dialkyl ammonium, such as NH2(C2H5,)2, and alkanol ammonium; such as NH3CH2CH2OH.

Salts of this invention are found to have unexpected properties. On parenteral administration they are definitely sedative and anesthetic in their physiological action and have decided analgesic properties. The minimum anesthetic dose of sodium l-m'ethylallyl napropyl thiobarbiturate, for example, is 40 mg. per kilogram of body weight when administered intravenously to rabbits, while the minimum anesthetic dose of sodium l-methylallyl n-butyl thiobarbiturate, when administered intravenously to rabbits, is 35 mg. per kilogram of body weight. The therapeutic ratio (M. L. D.-:-M. A. D.) upon intravenous administration to rabbits of both sodium salts is 2. The duration of action on intravenous administration to rabbits for the sodium l-methylallyl n-propyl thiobarbiturate is 96 minutes, while the duration of the sodium l-methylallyl n-butyl thiobarbiturate is 45 minutes. These properties :are decidedly unexpected in View of the fact that almost all of the salts of l-methylallyl alkyl thiobarbiturate acids produce tremors or convulsions. For example, sodium l-methyl allyl ethyl thiobarbiturate, sodium l-methylallyl isobutyl thiobambiturate, sodium l-methylallyl namyl thiobarbiturate, sodium l-methylallyl 2- methyl'butyl thiob'arbiturate, and sodium l-methylallyl 3-methylbutyl thiobarbiturate all produce either tremors or convulsions in rats, while the corresponding salts of the thiobarbiturate compounds of this invention produce anesthesia without any indication of tremors or convulsions. Moreover, some of the isomers of sodium l-methylallyl n-butyl thiobarbiturate produce convulsions or tremors when administered intraperitoneally to rats. For example, sodium l-methylallyl isobutyl thiobanbiturate, sodium crotyl nbutyl thiobarbiturate, and sodium crotyl isobutyl thiobarbiturate produce no anesthesia and cause either tremors or convulsions. Another isomer, sodium 2-methylallyl n-butyl thiobarbiturate, while producing anesthesia, causes convulsions when administered intraperitoneally to rats. Likewise, sodium crotyl n-propyl thiobarbiturate and sodium 2-methylallyl n-propyl thiobarbiturate, which are isomers of the l-methylallyl n- ;propyl thiobarbiturate, also produce convulsions. Both sodium l-methylallyl n-butyl thiobarbiturate and sodium l-methylallyl n-butyl thiobarbiturate cause no tremors or convulsions when administered intraperitone'ally in rats, but produoe a short effective anesthesia.

The l-methylallyl thiobarbituric compounds of this invention are prepared by either the malonicester method or the cyanacetic-ester method, but it is preferred that the malonic-ester method be employed. I

In [preparing the l-methylallyl thiobarbiturate compounds of this invention, it is desirable that the l-methylallyl halide (preferably chloride or bromide) used in preparing the l-methylallyl npropyl ethylmalonate or l-methylallyl n-butyl ethylmalonate, or the l-methylallyl ri-propyl ethylcyanacetate or the l-methylallyl n-butyl ethylcyanaoetate from which the desired l-methylallyl thiobarbituric acid is obtained, be substantially free from any isomer, particularlyfrom the crotyl halide into which the l -methylallyl halide partially isomerizes on standing to produce an equilibrium mixture. Therefore it is important that there be a separation of such an equilibrium mixture of halides to obtain therefrom substantially isomer-free the desired l-methylallyl halide (chloride or bromide) immediately before preparing the desired l-methylallyl alkyl ethylmalonate or l-methylallyl alkyl ethylcyanacetate; which separation of isomers may be formed by known methods. (Kharasch, Kritchevsky and Mayo, Journal Organic Chem, vol. 2, page 489, 1937-38; Winstein and Young, Journal Amer. Chem. Soc, vol; 58, page 104, 1936.)

M alom'c-estef method To prepare the disubstituted 1-methylallyl nipropyl ethylmalonate or l-methylallyl' n-butyl ethylmalonate, a 1methyl a1ly1 halide is con-' densed with n-propyl ethylmalonate or n-butyl ethylmalonate; or n-propyl halide or n-butyl halide with mono-l-methylallyl ethylmalonate in the presence of sodium ethylate in the manner customary for making :disubstituted malonic esters.

Ezrample.0ne mol of sodium is dissolved in from 10 to 12 times its weight of absolute alcohol under a reflux condenser. One mol of n-propyl ethyl-malonate is then added. Part of the alcohol that is used may then be removed as by vacuum distillation and then about 1.1 mols l-methylallyl chloride (or l-methylallyl bromide) are gradually added. The l-methylallyl chloride (or 1- methylallyl bromide) used is preferably isomerfree, as has already been pointed out. The mixture is refluxed for some hours, desirably until it no longer shows an alkaline reaction to moist litmus paper. Most of the alcohol remaining, whether or not some has previously been removed, is now removed by vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve out the sodium chloride (or bromide) present in it; and the oily layer, which contains the desired l-methylallyl n-propyl ethylmalonate, is separated and dried. This crude l-methylallyl n-propyl ethylmalonate is purified by fractional distillation in vacuo; and when purified is found to boil at 110-115 C., uncorrected, at about 4 mm. pressure. It is a substantially colorless liquid and is represented by the following formula:

( CH2=CHCH CO-OC2H CH3 CHaCHzCHz 0 O0 C2H5 In the foregoing example one mol of n-butyl ethylmalonate may be used instead of one mol of n-propyl ethylmalonate; in which case the malonic ester obtained is l-methylallyl n-butyl ethylmalonate which, when purified by fractional distillation, is found to boil at 120125 0., uncorrected, at about 4 mm. pressure. It is a substantially colorless liquid and is represented by the following formula:

( CH2=CHCH As has heretofore been indicated, instead of using n-propyl ethylmalonate or n-butyl ethylmalonate in reaction with l-methylallyl chloride (or l-methyllayl bromide) the mono-1- methylallyl ethylmalonate is reacted with npropyl chloride (or bromide or iodide) or nbutyl chloride (or bromide or iodide). In that case, however, the l-methylallyl ethylmalonate is preferably substantially isomer-free, for which purpose care should be taken in making it.

So far as is known, the l-methylallyl ethylmalonate is a new substance. It is made by condensing one mol of ethylmalonate with about 1.1 mols of l-methylallyl chloride '(or bromide) in the presence of a solution of 1 mol of sodium ethylate in absolute alcohol. chloride (or bromide should be substantially isomer-free. The mixture is refluxed for some hours, desirably until it no longer shows an alkaline reaction to moist litmus paper. The alcohol is now removed by vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve out the sodium chloride (or bromide) present in it and the oily layer, which contains the desired l-methylallyl ethylmalonate is separated and dried. The crude l-methylallyl ethylmalonate is purified by fractional distillation in vacuo and when purified is found to boil at about 110-115 C., uncorrected, at 13 mm. pressure. It is a substantially colorless liquid The l-methylallyl and may be represented by the following formula:

(4) CH2=CHCH 0 O0 C2115 CH3 From the l-methylallyl n-propyl ethylmalonate or the l-methylallyl n-butyl ethylmalonate prepared by either process outlined above, the 1- methylallyl n-propyl thiobarbituric acid and the l-methylallyl n-butyl thiobarbituric acid may be prepared by condensing the appropriate malonate with thiourea in the presence of a sodium alcoholate, such as sodium ethylate, as follows:

To prepare l-methylallyl n-propyl thiobarbituric acid:

Y n-propyl ethylmalonate.

Three mols of sodium are dissolved in 10 to 12 times its weight of absolute alcohol under a reflux condenser. To this mixture are added about 1.6 mols of thiourea and 1 mol of l-methylallyl The mixture is gently refluxed for about 15 to 20 hours, after which most of the alcohol is removed by vacuum distillation. The residue is dissolved in water and a sufficient amount of dilute acid, such as hydrochloric acid, is added to completely throw out of solution the l-methylallyl n-propyl thiobarbituric acid which has been formed. This 1- methylallyl n-propyl thiobarbituric acid usually comes out of solution in the form of an oil which solidifies on standing. This solid so obtained is separated as by filtration, is then dried and may be washed with gasoline; and is then purified by recrystallization, as from diluate ethyl alcohol.

This l-methylallyl n-propyl thiobarbituric acid is a whitish crystalline solid with a slight yellow tinge; melts at about 141-142 C., corrected; is insoluble in water and readily soluble in alcohol and in ether. It is represented by the following formula:

( CH2=CHCH C O-NH CH2 CHaCHaCH: CONH To prepare l-methylallyl n-butyl thiobarbituric acid, the procedure just outlined is followed, except that instead of employing 1 mol of l-methylallyl n-propyl ethylmalonate, 1 mol of l-methylallyl n-butyl ethylmalonate is employed. The resulting l-methylallyl n-butyl thiobarbituric acid is a white crystalline solid with a slight yellow tinge, melts at about 133-135 C., corrected, is insoluble in water and readily soluble in alcohol and in ether. It is represented by the following formula:

CyanaceticEster method When ethylcyanacetate is used instead of ethylmalonate in the preparation of 1-methylallyl n-propyl thiobarbituric acid, purified 1- methylallyl chloride (or bromide) may be reacted with n-propyl ethylcyanacetate, or n-propyl chloride (or bromide) may be reacted with l-methylallyl ethylcyanacetate. In using the latter procedure, 1 mol of sodium is dissolved in 10 to 12 times its weight of absolute ethyl alcohol under a reflux condenser and 1 mol of ethylcyanacetate is then added. The sodium ethylcyanacetate separates out as a solid at this stage, then about 1.1 mols of purified l-methylallyl chloride (or bromide) are added and the mixture is refluxed for about 15 hours. The alcohol is removed by Vacuum distillation, leaving an oily residue. Water is added to this residue to dissolve out the sodium chloride (or bromide) present in it; and the oily layer, which contains the desired l-methylallyl ethylcyanacetate, is separated and dried. This crude l-methylallyl ethylcyanacetate is purified by fractional distillation in vacuo. It is represented by the following formula:

(7) CH2=CHCH similar to that described above for the preparation of l-methylallyl ethylcyanacetate.

The l-methylallyl n-propyl ethylcyanacetate is represented by the following formula:

( CHF-CHCH COOC2H5 Ha CH3CH2CH2 ON The l-methylallyl n-propyl ethylcyanacetate may also be prepared from l-methylallyl chloride (or bromide) and n-propyl ethylcyanacetate. In this case the n-propyl ethylcyanacetate is prepared from ethylcyanacetate and n-propyl chloride (or bromide) in the presence of sodium ethylate, and the resulting n-propyl ethylcyanacetate condensed With the l-methylallyl chloride (or bromide) in the presence of sodium ethylate in the manner described above for the preparation of the l-methylallyl ethylcyanacetate.

When ethylcyanacetate is used in the preparation of l-methylallyl n-butyl thiobarbituric acid, purified l-methylallyl chloride (or bromide) may be reacted with n-butyl ethylcyanacetate, or nbutyl bromide (or chloride) may be reacted with l-methylallyl ethylcyanacetate to produce 1- methylallyl n-butyl ethylcyanacetate in the manner outlined above for producing l-methylallyl n-propyl ethylcyanacetate. From the disubstituted 1-methylallyl n-propyl ethylcyanacetate or l-methylallyl n-butyl ethylcyanacetate prepared by either procedure, l-methylallyl n-propyl thiobarbituric acid and l-methylallyl n-butyl thiobarbituric acid may be produced as follows:

To make l-methylallyl n-butyl thiobarbituric acid, 3 mols of sodium are dissolved in 10 to 12 times its Weight of absolute alcohol under a reflux condenser. To this mixture are added about 1.6 mols of thiourea and 1 mol of l-methylallyl n-butyl ethylcyanacetate. The mixture is gen- .tly refluxed for about 15 to hours, after which most of the alcohol is removed by vacuum distillation. The residue, which comprises sodium 1- methylallyl n-butyl imino thiobarbiturate, is dissolved in water and sufficient dilute acid, such as hydrochloric acid, is added to make the solution barely acid to litmus paper, which precipitates the l-methylallyl n-butyl imino thiobarbituric acid. Excess acid is undesirable because it will dissolve the l-methylallyl n-butyl imino thiobarbituric acid which has been formed, whereas if the solution is made just barely acid the 1- methylallyl n-butyl imino thiobarbituric acid separates out as a solid. This solid so obtained is separated as by filtration, is then dried, and is then purified by recrystallization as from dilute ethyl alcohol.

This l-methylallyl n-butyl imino thiobarbituric acid is a yellowish colored solid, melting at about 180-1 85 C., uncorrected, and is represented by the following formula:

( OH2=CHCH resented by the following formula:

(10) CH2=CHCH CONH CH3 CHaCHzCHa CNHNH On boiling this product with aqueous hydrochloric acid or aqueous alcoholic hydrochloric acid, the l-methylallyl n-propyl imino thiobarbituric acid is converted by hydrolysis into 1- methylallyl n-propyl thiobarbituric acid, which melts at about 141-142 C., corrected.

Thiobarbiturates may readily be obtained from the l-methylallyl n-propyl thiobarbituric acid and the l-methylallyl n-butyl thiobarbituric acid above described. These thiobarbiturates are represented by Formula 1 above with R representing n-propyl or n-butyl, as the case may be, and withXrepresenting an alkali metal, an equivalent of an alkaline-earth metal, ammonium, mono-alkyl ammonium, dialkyl ammonium, or alkanol ammonium. These thiobarbiturates maybe obtained by the reaction of the l-methylallyl npropyl thiobarbituric acid, or of the l-methylallyl n-butyl thiobarbituric acid in a suitable solvent with either the hydroxide or the ethylate of the desired inorganic base, or with ammonia, or with the desired alkyl or alkanol amine. The sodium salts, for instance, are represented by the following formulas:

(11) CHz=CHCH CO-NH Cs COIII/ OHaCHzCHzCHz The other alkali metal salts have the same general formula except for the substitution of the other metal for sodium. These salts are prepared in the general way of preparing the alkali metal salts from barbituric acids or thiobarbituric acids. The sodium salts are whitish solids, soluble in water and alcohol, and insoluble in ether. They are bitter tasting and their aqueous solutions are alkaline in reaction.

When these sodium salts are desired in stable form, sufliciently free from contaminants so that clear water solutions thereof suitable for intravenous injection may be obtained, they are produced by the methods disclosed in the U. S. Patent 1,856,792 issued to H. A. Shonle on May 3, 1932.

The ammonium and alkylamine and alkanolamine salts of l-methylallyl n-propyl thiobarbituric acid and of l-methylallyl n-butyl thiobarbituric acid may be produced by the reaction of those respective acids with ammonia or with the desired amine in the usual manner of producing ammonium or alkylamine or alkanolamine barbiturates and thiobarbiturates. Theformulas of these thiobarbiturates correspond in general to Formula 1 above except that NH4 or the proper substituted-ammonium radical is substituted for H at the point X of Formula 1.

What is claimed is:

1. A thiobarbituric compound which is represented by the following formula:

in which R is a radical selected from the class consisting of n-propyl and n-butyl radicals, and X is a member selected from the class consisting of hydrogen, the alkali metals, the equivalents of the alkaline-earth metals, ammonium, monoalkyl ammoniums. dialkyl ammoniums, and alkanol ammoniums.

'2. A l-methylallyl n-propyl thiobarbituric compound which is represented by the following formula:

in which X is a member selected from the class consisting of hydrogen, the alkali metals, the equivalents of the alkaline-earth metals, ammonium, mono-alkyl ammoniums, dialkyl ammoniums, and alkanol ammoniums.

3. A l-methylallyl n-butyl thiobarbituric compound which is represented by the following formula:

OH2=CHCH CO-NH Ha CHaCHzCHzCHz CO}\I X l-methylallyl n-butyl thiobar- Certificate of Correction Patent No. 2,293,770. August 25, 1942.

HORACE A. SHONLE ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Page 1, first column, line 44, for thiobarbiturate read tht'obarbitur'ic; and second column, line 12, for n-butyl read n-propyl; page 2, second column, line 36, for diluate read dilute; and lines 43 to 45, Formula 5, for that portion of the formula reading CH2=CHCH CH2 C CHsCHzC 2 read CH2=CHOH CH3 C CHsCHzCg page 4, second column, line 39, claim 6, for l-methylally read I-methylallyl; and that the said Letters Patent should be read With these corrections therein that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 20th day of October, A. D. 1942.

[SEAL] HENRY VAN ARSDALE,

Acting Commissioner of Patents. 

